Researchers developed a way of reprograming cells to use synthetic materials — provided by the team — to create artificial, working structures within or about the cells.
This approach may be a way to reprogram nerve cells to produce myelin-like protective polymers — large molecules made of many repeating units — around their axons to overcome the loss of myelin that marks multiple sclerosis (MS).
“We turned cells into chemical engineers of a sort, that use materials we provide to construct functional polymers that change their behaviors in specific ways,” Karl Deisseroth, MD, PhD, a study co-senior author and the D.H. Chen Professor of bioengineering and of psychiatry and behavioral sciences at Stanford University, said in a press release.
The new method — called genetically targeted chemical assembly, or GTCA — was described in the study, “Genetically targeted chemical assembly of functional materials in living cells, tissues, and animals,” published in the journal Science.
GTCA, which combines genetic engineering and polymer chemistry, was used to build artificial, bioelectric structures around specific nerve cells in mammals and in C. elegans, a tiny worm used as an animal model, to see whether it would change cell function.
The approach involved three steps. First, a modified and harmless adeno-associated virus (AAV) was used to deliver a gene with instructions to produce an enzyme called APEX2 to specific nerve cells. This was done in worms, living slices from mouse brains, and nerve cells from rat brains grown in the lab.
Second, the worms and the experimental tissues were immersed in a solution containing billions of small biocompatible molecules with either conductive (those allowing electric charges to flow easily) or insulating (those that do the opposite) properties.
Third, an extremely low dose of hydrogen peroxide was added to the solution. In the presence of hydrogen peroxide, the APEX2 enzyme promoted the formation of polymers from these small electric molecules to form a mesh-like material around the target nerve cells.
The researchers then were able to build artificial biocompatible nets — promoting (conductive) or not (insulative) the passage of electric currents — around the nerve cells.
These new structures were found to change the function of the targeted cells, with conductive nets promoting a faster transmission of electric signals (firing), and insulative nets slowing a cell’s firing of signals.
Notably, these distinct nets around nerve cells in worms changed the animals’ movements, at least in certain muscle groups, depending on whether the nets were insulative or conductive.
This cell-targeted technology was also found to be non-toxic in both worms and live slices from mouse brain, and to have lasting effects: high levels of the APEX2-driven polymers were still detected four weeks after genetic modification.
Researchers emphasized that GTCA should work with other types of cells, in addition to nerve cells.
“We’ve developed a technology platform that can tap into the biochemical processes of cells throughout the body,” said Zhenan Bao, PhD, the study’s other co-senior author and K.K. Lee Professor of chemical engineering at Stanford.
Researchers hope to further explore their new method’s potential to produce a wide range of working molecules and structures, promoted by different chemical signals, that might restore cell function in disorders like MS, autism, or epilepsy.
“By integrating engineered-enzyme targeting and polymer chemistry, we genetically instructed specific living neurons to guide chemical synthesis of electrically functional (conductive or insulating) polymers at the plasma membrane,” the team wrote.
“Electrophysiological and behavioral analyses confirmed that rationally designed, genetically targeted assembly of functional polymers not only preserved neuronal viability but also achieved remodeling of membrane properties and modulated cell type–specific behaviors in freely moving animals,” their study concluded.
“This approach may enable the creation of diverse, complex, and functional structures and materials within living systems.”
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